Department of Genetics, Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13130-4. doi: 10.1073/pnas.1110081108. Epub 2011 Jul 25.
Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with growth retardation, mental retardation, and immunodeficiency resulting from a hemizygous deletion of the short arm of chromosome 4, called the WHS critical region (WHSC). The WHSC1 gene is located in this region, and its loss is believed to be responsible for a number of WHS characteristics. We identified WHSC1 in a genetic screen for genes involved in responding to replication stress, linking Wolf-Hirschhorn syndrome to the DNA damage response (DDR). Here, we report that the WHSC1 protein is a member of the DDR pathway. WHSC1 localizes to sites of DNA damage and replication stress and is required for resistance to many DNA-damaging and replication stress-inducing agents. Through its SET domain, WHSC1 regulates the methylation status of the histone H4 K20 residue and is required for the recruitment of 53BP1 to sites of DNA damage. We propose that Wolf-Hirschhorn syndrome results from a defect in the DDR.
沃尔夫-赫希霍恩综合征（WHS）是一种与生长迟缓、智力障碍和免疫缺陷相关的畸形综合征，由 4 号染色体短臂的半合缺失引起，称为 WHS 关键区域（WHSC）。WHSC1 基因位于该区域，其缺失被认为是许多 WHS 特征的原因。我们在参与复制应激反应的基因的遗传筛选中鉴定出 WHSC1，将沃尔夫-赫希霍恩综合征与 DNA 损伤反应（DDR）联系起来。在这里，我们报告 WHSC1 蛋白是 DDR 途径的成员。WHSC1 定位于 DNA 损伤和复制应激部位，并且对于抵抗许多 DNA 损伤和复制应激诱导剂是必需的。通过其 SET 结构域，WHSC1 调节组蛋白 H4 K20 残基的甲基化状态，并需要募集 53BP1 到 DNA 损伤部位。我们提出，沃尔夫-赫希霍恩综合征是由 DDR 缺陷引起的。
